Synthesis, aggregation, and neurotoxicity of the alzheimerʹs Aß1-42 amyloid peptide and its isoaspartyl isomers

Amyloid Aß1-42 peptide (Aß1-42) and its isomers with an isoaspartyl residue at position 7 or 23 [Aß1-42(isoAsp7) and Aß1-42(isoAsp23)] were synthesized in high purity by the Fmoc-solid phase technique, followed by HPLC on a silica-based reversed-phase column under the basic conditions. Importantly, Aß1-42(isoAsp23) aggregated more strongly than native Aß1-42 and showed significant neurotoxicity, while the aggregation ablility and neurotoxicity of Aβ1-42(isoAsp7) vas weak. This suggests that the isomerization of the aspartyl residues plays an important role in fibril formation in Alzheimerʹs disease.